Feasibility and safety of endoscopic full-thickness resection for submucosal tumors in the upper gastrointestinal tract, including predominantly extraluminal submucosal tumors (with video).

OBJECTIVES: Endoscopic full-thickness resection (EFTR) for submucosal tumors (SMTs) has been technically challenging. This retrospective study aimed to evaluate the feasibility, safety, and efficacy of EFTR for upper gastrointestinal (GI) SMTs, including extraluminal lesions. METHODS: We retrospectively investigated 232 patients with SMTs who underwent EFTR from January 2014 to August 2023. Clinicopathologic characteristics, procedure-related parameters, adverse events (AEs), and follow-up outcomes were assessed in all patients. RESULTS: The en-bloc resection and en-bloc with R0 resection rates were 98.7% and 96.1%, respectively. The average endoscopic tumor size measured 17.2 ± 8.7 mm, ranging from 6 to 50 mm. The resection time and suture time were 49.0 ± 19.4 min and 22.5 ± 11.6 min, respectively. In all, 39 lesions (16.8%) exhibited predominantly extraluminal growth. Gastrointestinal stromal tumors (GISTs) were the predominant pathology, accounting for 78.4% of the cases. Twenty-one patients (9.1%) encountered complications, including pneumothorax (1/232, 0.43%), hydrothorax (1/232, 0.43%), localized peritonitis (3/232, 1.29%), and fever (16/232, 6.9%). Although the incidence of postoperative fever was notably higher in the predominantly extraluminal group (7/39, 17.9%) compared to the predominantly intraluminal group (9/193, 4.7%, P = 0.008), there were no significant differences in outcomes of the EFTR procedure. No instances of recurrence were observed during the mean follow-up period of 3.7 ± 2.3 years. CONCLUSION: EFTR was found to be feasible, safe, and effective for resecting upper GI SMTs, including lesions with predominantly extraluminal growth. Further validation in a prospective study is warranted.

Titin as a potential novel therapeutic target in colorectal cancer.

Colorectal cancer (CRC) is identified as a primary cause of death around the world. The current chemotherapies are not cost-effective. Therefore, finding novel potential therapeutic target is urgent. Titin (TTN) is a muscle protein that is critical in hypertrophic cardiomyopathy. However, its role in CRC is not well understood. The study focused on exploring the possible role of TTN in CRC carcinogenesis. TTN mRNA and protein expression levels presented an obvious downregulation in CRC tissue samples, relative to normal control (p < 0.05). TTN expression significantly correlated with the clinical stage (normal vs. Stage 1, p < 0.05; normal vs. Stage 4, p < 0.05), node metastasis (normal vs. N1, p < 0.05; N1 vs. N2, p < 0.05), histological type (normal vs. adenocarcinoma, p < 0.05), race (Caucasian vs. Asian, p < 0.05; African-American vs. Asian, p < 0.05) and TP53 mutation (normal vs. TP53 mutation, p < 0.05), considering The Cancer Genome Atlas database. However, for patients who had higher TTN expression, the overall survival was remarkably shorter than patients who had low TTN expression. Furthermore, TTN was lowly expressed in four CRC cell lines. TTN overexpression facilitated CRC cells in terms of the proliferation, metastasis and invasion. Based on gene set enrichment analysis, the ERB pathway might be responsible for TTN-related CRC. Besides, TTN was involved in the response to azacitidine. Overall, TTN might serve as a potential novel therapeutic target for treating and overcoming chemotherapy resistance in CRC.

Oncogenic LINC00857 recruits TFAP2C to elevate FAT1 expression in gastric cancer.

FAT atypical cadherin 1 (FAT1) is a mutant gene frequently found in human cancers and mainly accumulates at the plasma membrane of cancer cells. Emerging evidence has implicated FAT1 in the progression of gastric cancer (GC). This study intended to identify a regulatory network related to FAT1 in GC development. Upregulated expression of FAT1 was confirmed in GC tissues, and silencing FAT1 was observed to result in suppression of GC cell oncogenic phenotypes. Mechanistic investigation results demonstrated that FAT1 upregulated AP-1 expression by phosphorylating c-JUN and c-FOS, whereas LINC00857 elevated the expression of FAT1 by recruiting a transcription factor TFAP2C. Functional experiments further suggested that LINC00857 enhanced the malignant biological characteristics of GC cells through TFAP2C-mediated promotion of FAT1. More importantly, LINC00857 silencing delayed the tumor growth and blocked epithelial-mesenchymal transition in tumor-bearing mice, which was associated with downregulated expression of TFAP2C/FAT1. To conclude, LINC00857 plays an oncogenic role in GC through regulating the TFAP2C/FAT1/AP-1 axis. Therefore, this study contributes to extended the understanding of gastric carcinogenesis and LINC00857 may serve as a therapeutic target for GC.

Antibiotic-induced gut microbiota dysbiosis has a functional impact on purine metabolism.

BACKGROUND: Dysbiosis of the gut microbiota is closely linked to hyperuricemia. However, the effect of the microbiome on uric acid (UA) metabolism remains unclear. This study aimed to explore the mechanisms through which microbiomes affect UA metabolism with the hypothesis that modifying the intestinal microbiota influences the development of hyperuricemia. RESULTS: We proposed combining an antibiotic strategy with protein-protein interaction analysis to test this hypothesis. The data demonstrated that antibiotics altered the composition of gut microbiota as UA increased, and that the spectrum of the antibiotic was connected to the purine salvage pathway. The antibiotic-elevated UA concentration was dependent on the increase in microbiomes that code for the proteins involved in purine metabolism, and was paralleled by the depletion of bacteria-coding enzymes required for the purine salvage pathway. On the contrary, the microbiota with abundant purine salvage proteins decreased hyperuricemia. We also found that the antibiotic-increased microbiota coincided with a higher relative abundance of bacteria in hyperuricemia mice. CONCLUSIONS: An antibiotic strategy combined with the prediction of microbiome bacterial function presents a feasible method for defining the key bacteria involved in hyperuricemia. Our investigations discovered that the core microbiomes of hyperuricemia may be related to the gut microbiota that enriches purine metabolism related-proteins. However, the bacteria that enrich the purine salvage-proteins may be a probiotic for decreasing urate, and are more likely to be killed by antibiotics. Therefore, the purine salvage pathway may be a potential target for the treatment of both hyperuricemia and antibiotic resistance.

Peripheral blood T-lymphocyte subsets are potential biomarkers of disease severity and clinical outcomes in patients with ulcerative colitis: a retrospective study.

BACKGROUND: Ulcerative colitis (UC) is considered an immune-mediated disease. The disorder of T-lymphocyte subsets plays an important role in the pathogenesis of UC. The aim of this study was to evaluate the significance of peripheral blood T-lymphocyte subsets in assessing disease severity and predicting clinical outcomes in UC patients. METHODS: The retrospective case-control study was performed in 116 UC patients with active disease and 90 healthy controls (HC). The UC patients included were followed up for 180 days. Analyses of t-test, Spearman's correlation coefficient, multivariable Cox regression analysis, receiver operating characteristic (ROC) curves and cumulative survival analysis were done. RESULTS: The UC patients had lower proportions of CD4+T cells (42.85%±9.77% vs 45.71%±7.94%, P=0.021) and higher proportion of CD8+T cells (27.88%±8.86% vs 25.00%±6.47%, P=0.008) than HC. The severely active UC patients had higher proportion of CD3+HLA-DR+ T cells (8.83%±6.55% vs 2.80%±1.55%, P<0.001; 8.83%±6.55% vs 4.06%±5.01%, P<0.001) and CD8+T cells (31.35%±8.49% vs 26.98%±7.98%, P=0.029; 31.35%±8.49% vs 25.46%±9.15%, P=0.003) than mild and moderate group, whereas lower proportion of CD4+CD25+T cells (2.86%±1.35% vs 3.46%±1.07%, P=0.034) than mild group and CD4+T cells (40.40%±9.36% vs 44.73%±10.39%, P=0.049) than moderate group. The area under the curve (AUC) of CD3+HLA-DR+ T cells for assessing severely active UC was 0.885, with the cut-off value of 5.33%. The sensitivity was 76.32% and specificity was 89.74%. The combination of CD3+HLA-DR+ T cells and CRP had stronger assessment value with AUC of 0.929. The AUC of CD8+T cells, CD4+/CD8+ ratio and CD4+CD25+T cells for assessing disease severity was 0.677, 0.669 and 0.631 respectively. Within the 180 days follow-up, 24 patients (20.69%) had UC-related readmission or surgery, with higher proportion of CD3+HLA-DR+ T cells (10.66%±9.52% vs 3.88%±2.56%, P=0.003) and CD8+T cells (31.19%±10.59% vs 27.01%±8.20%, P=0.039) than those without readmission and surgery. The proportion of CD3+HLA-DR+ T cells was the independent predictor of UC-related readmission or surgery (HR=1.109, P=0.002). The AUC of CD3+HLA-DR+ T cells for predicting readmission or surgery was 0.796 with the cut-off value of 5.38%. UC patients with CD3+HLA-DR+T cells proportion>5.38% had a shorter time to readmission or surgery (log-rank test, P<0.001). CONCLUSIONS: The combination of CD3+HLA-DR+T cells and CRP may be potential biomarker of disease severity in UC patients. The high proportion of CD3+HLA-DR+T cells may be associated with an increased risk of readmission or surgery in UC patients.

Chrysin enhances antitumour immunity response through the IL-12-STAT4 signal pathway in the B16F10 melanoma mouse model.

Chrysin (CHR) is a flavonoid with extensive pharmacological activity. The molecular formula of CHR is C15 H10 O4 . CHR is reported to have antioxidative, antitumour and antiviral functions. To evaluate its potential function as a vaccine adjuvant, we prepared a melanoma vaccine using a soluble protein extract of B16F10 melanoma cells as antigen and CHR as an adjuvant. The melanoma model was developed after two immunizations, and it was discovered that combining B16F10 soluble protein antigen-mixed CHR vaccine could inhibit tumour growth in the mouse model, and the overall survival rate was higher than that of the B16F10 antigen vaccine alone. In vivo and in vitro experiments were conducted to determine whether CHR functioned as an adjuvant by activating antigen-presenting cells (APCs). We discovered that CHR activated APCs both in vivo and in vitro and may enhance Th1 cell function by activating the IL12-STAT4 signal pathway, thereby enhancing the antitumour response of cytotoxic T lymphocytes (CTLs) in vivo. Next, to verify the critical role of CD8+ T cells in suppressing melanoma development, we transplanted CD8+ T cells from immunized mice to B16F10 tumour-bearing mice and discovered that the survival rate of tumour-bearing mice was significantly prolonged. In summary, our experimental results indicate that CHR can be used as a potential adjuvant to enhance antigen immunogenicity, inhibit B16F10 tumour growth in mice and improve tumour immune response.

Poorly differentiated cluster grade-a vital predictor for lymph node metastasis and oncological outcomes in patients with T1 colorectal cancer: a retrospective study.

BACKGROUND: T1 colorectal cancers have a low lymph node metastasis rate and good prognosis. Thus, endoscopic resection is an attractive choice. This study aimed to describe the value of poorly differentiated cluster grade in identifying endoscopically curable T1 colorectal cancers. METHODS: We included 183 T1 colorectal cancer patients who underwent curative resection. Univariate and multivariate logistic regressions were used to identify lymph node metastasis predictors. The Akaike information criterion was used to determine whether poorly differentiated cluster grade was the best predictor. Backward regression was used to screen the variables. Survival analyses were conducted to determine the prognostic predictive power of poorly differentiated cluster grade. Correlations among predictors and concordance between our pathologists were also investigated. RESULTS: Poorly differentiated cluster grade was an independent predictor for lymph node metastasis (adjusted odds ratio [OR]G 3 = 0.001; 95% confidence interval [95% CI]G 3 = < 0.001, 0.139) in T1 colorectal cancer patients; moreover, it had the best predictive value (AIC = 61.626) among all indicators. It was also screened for inclusion in the predictive model. Accordingly, a high poorly differentiated cluster grade independently indicated shorter overall survival (hazard ratio [HR]G 2 = 4.315; 95% CIG 2 = 1.506, 12.568; HRG 3 = 5.049; 95% CIG 3 = 1.326, 19.222) and disease-free survival (HRG 3 = 6.621; 95% CIG 3 = 1.472, 29.786). CONCLUSIONS: Poorly differentiated cluster grade is a vital reference to manage T1 colorectal cancer. It could serve as an indicator to screen endoscopically curable T1 colorectal cancers.

Body Composition Changes and Related Factors in Patients with Ulcerative Colitis: A Retrospective Single-Center Study in China.

BACKGROUND This study retrospectively explored body composition changes and related factors in patients with ulcerative colitis (UC). MATERIAL AND METHODS Patients with UC and healthy individuals who served as the healthy control at the Affiliated Hospital of Qingdao University September 2017 to August 2018 were retrospectively analyzed. Clinical data and laboratory examination indexes were collected. The skeletal muscle area (SMA) of the third lumbar vertebra cross-section, the subcutaneous fat area (SFA), and the visceral fat area (VFA) at the umbilical level were measured by computed tomography (CT), and the skeletal muscle index (SMI) was calculated to evaluate the loss of muscle mass. RESULTS Data from a total of 80 patients (median age, 49.49 years; 44 [55%] men) with active UC in the UC group and 80 healthy people age- and sex-matched in the healthy control group were collected. The incidence of low SMI and malnutrition was remarkably higher in the UC group than in the healthy control group (P<0.05). Low SMI was observed in 62.5% of UC patients who had a normal body mass index. Based on classification by the Truelove and Witts' criteria, the prevalence of malnutrition in severe UC patients was remarkably higher than that in mild and moderate UC patients (P<0.05). Based on the disease extent, the prevalence of low SMI in E3 type UC was dramatically higher than that in E2 type (P=0.028). CONCLUSIONS Loss of muscle mass was related to disease extent in patients with UC. Loss of muscle mass is more likely to be associated with malnutrition.

GPR43 Suppresses Intestinal Tumor Growth by Modification of the Mammalian Target of Rapamycin Complex 1 Activity in ApcMin/+ Mice.

OBJECTIVE: G protein-coupled receptor 43 (GPR43), a receptor for short-chain fatty acids, plays a role in suppressing tumor growth; however, the detailed underlying mechanism needs to be comprehensively elucidated. In this study, we investigated the role of GPR43 in inhibiting tumor growth using ApcMin/+, a murine model of intestinal tumors. MATERIALS AND METHODS: Using GPR43-/- ApcMin/+ and GPR43+/- ApcMin/+ mice, the number of tumors was analyzed at the end of the experimental period. Immunohistochemistry, quantitative polymerase chain reaction, and Western blotting were performed to analyze cellular proliferation and proliferation-associated signal pathways. RESULTS: Our results revealed that GPR43 deficiency resulted in increased tumor numbers in ApcMin/+ mice. Ki67 was highly expressed in GPR43-/- mice (p > 0.05). Increased expression levels of proinflammatory cytokines, including interleukin-6 and tumor necrosis factor-α, and amino acid transporters were not observed in GPR43-deficient mice compared to GPR43-sufficient mice. Furthermore, GPR43-deficient tumor tissues showed enhanced mammalian target of rapamycin-mediated phosphorylated ribosomal protein S6 kinase beta-1 (p > 0.05) and phosphorylated eukaryotic translation initiation factor 4E-binding protein 1 (p > 0.05), but not Akt (protein kinase B) phosphorylation (p = 0.7088). CONCLUSION: Collectively, GPR43 affords protection against tumor growth at least partly through inhibition of the mammalian target of rapamycin complex 1 pathway.

The contribution of intestinal Streptococcus to the pathogenesis of diabetic foot ulcers: An analysis based on 16S rRNA sequencing.

In this study, we intend to determine the microbial communities that are differentially expressed in diabetic foot ulcers (DFUs) from the view of species abundance difference and compositions. The EMBL-EBI database and QIIME2 platform were used to obtain and process 16S rRNA sequencing data of normal healthy and DFU samples. The LEfSe software was utilised to retrieve key intestinal bacteria differentially expressed in DFUs. Additionally, PICRUSt2, FAPROTAX and BugBase functional analyses were performed to analyse the potential microbial functions and related metabolic pathways. The correlations between intestinal microbiota and clinical indexes were evaluated using the Spearman correlation analysis. Significant differences existed in intestinal microbiota between DFU and normal healthy samples regarding species abundance difference and compositions at Kingdom, Phylum, Class, Order, Family, Genus and Species levels. Seven microbiota were demonstrated differentially expressed in DFUs that contained Bacteroidaceae, Prevotellaceae, Streptococcaceae, Lactobacillales, Bacilli, Veillonellaceae and Selenomonadales. Insulin signalling pathway may be the key pathway related to the functional significance of Streptococcus and Bacillus in the DFUs. The intestinal microbiota in DFUs exhibited susceptibility to sulphur cycling while displaying pathogenic potential. Last but not least, a close relationship between Streptococcus and the occurrence of DFUs was revealed. Taken together, this study mainly demonstrated the high abundance of Streptococcus in DFUs and its correlation with the disease occurrence.

Endoscopic ultrasound-guided drainage to abdominal abscess: A systematic review and meta-analysis.

Background: Ultrasound (US)- or computed tomography-guided drainage for abdominal abscess is currently the first-line options for drainage, but both options have disadvantages. Patients without adequate windows for drainage mostly undergo surgical drainage. However, surgical drainage is invasive and expensive. Endoscopic US (EUS)-guided drainage is a minimally invasive alternative for abdominal abscess, but there is less consensus on its efficacy, safety and complications. This meta-analysis aims to evaluate EUS-guided drainage for abdominal abscess. Materials and Methods: We retrieved relevant papers on EUS-guided drainage for abdominal abscess from the PubMed, Cochrane Library, Web of Science and EMBASE databases. Each paper was reviewed, and data were extracted. We used R software version 3.6.3 to perform the meta-analysis. Fixed effects models were used for merging data. Results: A total of 11 papers met the inclusion criteria, with a total sample population of 264 patients. The meta-analysis showed that the pooled clinical success rate was 90% (95% confidence interval [CI], 0.85-0.95), the technical success rate was 99% (95% CI, 0.97-1.00) and the recurrence rate was 1% (95% CI, 0.00-0.03). Three studies reported the complications, including perforation, bleeding and stent migration; none of the other eight studies reported complications. There were no significant differences between subgroups. There was no publication bias in either the clinical or the technical success rates. Conclusions: This meta-analysis showed that EUS-guided drainage for abdominal abscess was effective and safe, with an excellent technical success rate. In addition, EUS-guided drainage could be used for abscesses with complex anatomy. Nevertheless, complications and stent type should be considered.

Long intergenic noncoding RNA 00908 promotes proliferation and inhibits apoptosis of colorectal cancer cells by regulating KLF5 expression.

Long intergenic noncoding RNAs (lincRNAs) play a vital role in the occurrence and progression of cancer. The mechanism of lincRNAs in colorectal cancer (CRC) has not been fully elucidated. In this context, an integrated comparative long noncoding RNA (lncRNA) microarray technology was used to determine the expression profile of lncRNAs in CRC. The roles of LINC00908 are unclear. We found that LINC00908 was significantly upregulated in CRC. Inhibition of LINC00908 resulted in reduced cell proliferation and G1 cell cycle arrest, which was mediated by cyclin D1, cyclin-dependent kinase 4, and phosphorylated retinoblastoma. Moreover, inhibition of LINC00908-induced apoptosis through the intrinsic apoptosis signaling pathway, as shown by the activation of caspase-9 and caspase-3. Mechanistically, miR-143-3p directly bound to LINC00908. miR-143-3p expression was negatively correlated with LINC00908 expression in CRC tissue. Functional experiments revealed opposing roles for miR-143-3p and LINC00908, suggesting that LINC00908 negatively regulates miR-143-3p. Mechanistically, miR-143-3p directly targets LINC00908. The KLF5 inhibitor ML264 affected proliferation and apoptosis, indicating that LINC00908 may act as a competing endogenous RNA to facilitate the expression of the miR-143-3p target gene KLF5. Thus, LINC00908 has an important proliferative and antiapoptotic role in CRC by regulating the cell cycle and intrinsic apoptosis. LINC00908 could be a potential biomarker and a new therapeutic target for CRC.

LINC00511-dependent inhibition of IL-24 contributes to the oncogenic role of HNF4α in colorectal cancer.

Hepatocyte nuclear factor 4 α (HNF4α) is an important transcription factor that acts as a pro-proliferative mediator during tumorigenesis, yet its function in colorectal cancer (CRC) remain unclear. Hence, this study aims to explore roles that HNF4α plays in the CRC development. RNA quantification analysis was conducted to characterize the expression pattern of long intergenic noncoding RNA 00511 (LINC00511)/HNF4α/IL-24 in CRC tissues and cell lines. Using gain- and loss-of-function approaches, effects of HNF4α/LINC00511/IL-24 axis on biological processes such as proliferative, migrating, invading, apoptotic, and tumorigenic functions of CRC cells were evaluated. We further identified the interactions among HNF4α/LINC00511/EZH2/IL-24 using RNA binding protein immunoprecipitation, RNA pull-down along with chromatin immunoprecipitation (ChIP). LINC00511 was an upregulated lncRNA in CRC tissues and cells, which played an oncogenic role by strengthening the malignant phenotypes of CRC cells. LINC00511 downregulated IL-24 expression by interacting with EZH2. HNF4α could enhance LINC00511 transcription in an epigenetic manner, which finally accelerated cancer progression and tumorigenesis through LINC00511-mediated inhibition of IL-24. Those data together demonstrated the contribution of HNF4α to the progression of CRC through mediating the LINC00511/EZH2/IL-24 axis. Hence, our study provides a promising therapeutic target for CRC.NEW & NOTEWORTHY Our findings on the roles of hepatocyte nuclear factor 4 α/long intergenic noncoding RNA 00511/IL-24 axis provide new insights into the CRC and offer potential targets for translational applications.

Risk of Lymph Node Metastasis and Feasibility of Endoscopic Treatment in Ulcerative Early Gastric Cancer.

BACKGROUND: When the risk of lymph node metastasis (LNM) is considered minimal in patients with early gastric cancer (EGC), endoscopic submucosal dissection (ESD) is an effective alternative to radical resection. This study aims to estimate the feasibility of ESD for EGC with ulceration. PATIENTS AND METHODS: We retrospectively reviewed data from 691 patients who underwent gastrectomy for EGC with ulceration. Subsequently, a stratification system for lesions was created based on the expanded ESD criteria, and the associations between the subgroups and the rate of LNM were analyzed. RESULTS: LNM was confirmed in 16.5% (114/691) of patients. Univariate analysis demonstrated that age, sex, tumor size, macroscopic features, depth of invasion, tumor differentiation, Lauren type, lymphovascular invasion (LVI), and perineural invasion were associated with LNM. Multivariate analysis showed that LVI [odds ratio (OR) = 16.761, P < 0.001], SM1 invasion (OR = 2.159, P = 0.028), and SM2 invasion (OR = 3.230, P < 0.001) were independent risk factors for LNM. LNM occurred in undifferentiated mucosal tumors, with ulceration being 1.7% (2/116) when the lesion was smaller than 20 mm. Further stratification revealed that among lesions < 30 mm in size, undifferentiated tumors with SM1 invasion had a higher rate of LNM and a lower disease-free survival rate than differentiated tumors with SM1 invasion and tumors limited to the mucosal layer. CONCLUSIONS: Depth of invasion and LVI were strongly associated with LNM in ulcerative EGC. Endoscopic resection may be applicable for undifferentiated mucosal ulcerative EGC < 30 mm in size, and additional investigation is needed to evaluate its safety.

Inulin supplementation ameliorates hyperuricemia and modulates gut microbiota in Uox-knockout mice.

PURPOSE: Inulin is a type of fermentable dietary fiber, which is non-digestible, and can improve metabolic function by modulating intestinal microbiota. This study aimed to evaluate the role of inulin in hyperuricemia and microbial composition of the gut microbiota in a mouse model of hyperuricemia established through knockout of Uox (urate oxidase) gene. METHODS: KO (Uox-knockout) and WT (wild-type) mice were given inulin or saline by gavage for 7 weeks. The effect of inulin to combat hyperuricemia was determined by assessing the changes in serum UA (uric acid) levels, inflammatory parameters, epithelial barrier integrity, fecal microbiota alterations, and SCFA (short-chain fatty acid) concentrations in KO mice. RESULTS: Inulin supplementation can effectively alleviate hyperuricemia, increase the expressions of ABCG2 in intestine, and downregulate expression and activity of hepatic XOD (xanthine oxidase) in KO mice. It was revealed that the levels of inflammatory cytokines and the LPS (lipopolysaccharide) were remarkably higher in the KO group than those in the WT group, indicating systemic inflammation of hyperuricemic mice, but inulin treatment ameliorated inflammation in KO mice. Besides, inulin treatment repaired the intestinal epithelial barrier as evidenced by increased levels of intestinal TJ (tight junction) proteins [ZO-1 (zonula occludens-1) and occluding] in KO mice. Moreover, serum levels of uremic toxins, including IS (indoxyl sulfate) and PCS (p-cresol sulfate), were reduced in inulin-treated KO mice. Further investigation unveiled that inulin supplementation enhanced microbial diversity and raised the relative abundance of beneficial bacteria, involving SCFAs-producing bacteria (e.g., Akkermansia and Ruminococcus). Additionally, inulin treatment increased the production of gut microbiota-derived SCFAs (acetate, propionate and butyrate concentrations) in KO mice, which was positively correlated with the effectiveness of hyperuricemia relief. CONCLUSIONS: Our findings showed that inulin may be a promising therapeutic candidate for the treatment of hyperuricemia. Moreover, alleviation of hyperuricemia by inulin supplementation was, at least, partially conciliated by modulation of gut microbiota and its metabolites.

Potential methods for improving the efficacy of mesenchymal stem cells in the treatment of inflammatory bowel diseases.

Inflammatory bowel diseases (IBD) are a group of chronic recurrent gastrointestinal inflammatory diseases, including ulcerative colitis (UC), Crohn's disease (CD) and IBD unclassified. The pathogenesis may be related to the mucosal immune dysfunction in genetically susceptible hosts affected by environmental factors. Current therapeutic agents mainly include aminosalicylates, corticosteroids, immunosuppressive drugs and novel biological agents. The purpose of treatment is to suppress inflammation and prevent irreversible structural damage. However, long-term application of these drugs may lead to multiple adverse effects and is not always effective. Mesenchymal stem cells (MSCs) are multipotent progenitors with low immunogenicity, which can be obtained and expanded easily. They play an important role in regulating immune responses and repairing damaged tissues in vivo. Therefore, MSCs are considered to be a promising option for the treatment of IBD. Nonetheless, there are many factors that can reduce the efficacy of MSCs, such as gradual deterioration of functional stem cells with age, low recruitment and persistence in vivo and different routes of administration. In recent years, researchers have been able to improve the efficacy of MSCs by pretreatment, genetic modification or co-application with other substances, as well as using different tissue-derived cells, administration methods or doses. This article reviews these methods to provide references for more effective application of MSCs in the treatment of IBD in the future.

The anti-cancer effects of fucoidan: a review of both in vivo and in vitro investigations.

Fucoidan is a kind of the polysaccharide, which comes from brown algae and comprises of sulfated fucose residues. It has shown a large range of biological activities in basic researches, including many elements like anti-inflammatory, anti-cancer, anti-viral, anti-oxidation, anticoagulant, antithrombotic, anti-angiogenic and anti-Helicobacter pylori, etc. Cancer is a multifactorial disease of multiple causes. Most of the current chemotherapy drugs for cancer therapy are projected to eliminate the ordinary deregulation mechanisms in cancer cells. Plenty of wholesome tissues, however, are also influenced by these chemical cytotoxic effects. Existing researches have demonstrated that fucoidan can directly exert the anti-cancer actions through cell cycle arrest, induction of apoptosis, etc., and can also indirectly kill cancer cells by activating natural killer cells, macrophages, etc. Fucoidan is used as a new anti-tumor drug or as an adjuvant in combination with an anti-tumor drug because of its high biological activity, wide source, low resistance to drug resistance and low side effects. This paper reviews the mechanism by which fucoidan can eliminate tumor cells, delay tumor growth and synergize with anticancer chemotherapy drugs in vitro, in vivo and in clinical trials.

microRNA-365 inhibits YAP through TLR4-mediated IRF3 phosphorylation and thereby alleviates gastric precancerous lesions.

BACKGROUND: Gastric carcinoma (GC) is currently one of the most common malignant tumors of the digestive system, and gastric precancerous lesions play a vital role in studying the mechanism of GC. Multiple microRNAs (miRNAs) have been documented to be potential biomarkers to indicate progression of gastric precancerous lesions. In this study, we explained the anti-cancer effect of miR-365 in gastric precancerous lesions via regulation of the TLR4/IRF3/YAP/CDX2 axis. METHODS: miR-365, TLR4, CDX2 and IPF3 expression was determined in GC and atrophic gastritis tissues and cells. After transfection of shRNA and overexpression plasmids, in vitro experiments detected the alteration of cell viability, apoptosis and inflammatory factors. Bioinformatics analysis, Co-IP and dual luciferase reporter gene assay were conducted to evaluate the binding between miR-365 and TLR4 as well as IRF3 and YAP. Rat models were established to explore the effect of the miR-365 and TLR4 on gastric precancerous lesions. RESULTS: miR-365 was poorly expressed in GC and atrophic gastritis tissues and GC cell lines, while TLR4, CDX2 and IRF3 were overexpressed. Of note, miR-365 was indicated to target TLR4 and thereby suppressed cancer progression and increased hemoglobin content. Interestingly, silencing of TLR4 was accompanied by decreased IRF3 phosphorylation and reduced expression with less binding between CDX2 and IRF3. Downregulation of YAP resulted in declined CDX2 expression in cancer cells. Moreover, the inhibitory role of miR-365 was further confirmed in animal models. CONCLUSION: Taken together, miR-365-mediated TLR4 inhibition reduces IRF3 phosphorylation and YAP-mediated CDX2 transcription to impede progression of gastric precancerous lesions.

Concordance Study Between IBM Watson for Oncology and Clinical Practice for Patients with Cancer in China.

BACKGROUND: IBM Watson for Oncology (WFO), which can use natural language processing to evaluate data in structured and unstructured formats, has begun to be used in China. It provides physicians with evidence-based treatment options and ranks them in three categories for treatment decision support. This study was designed to examine the concordance between the treatment recommendation proposed by WFO and actual clinical decisions by oncologists in our cancer center, which would reflect the differences of cancer treatment between China and the U.S. PATIENTS AND METHODS: Retrospective data from 362 patients with cancer were ingested into WFO from April 2017 to October 2017. WFO recommendations were provided in three categories: recommended, for consideration, and not recommended. Concordance was analyzed by comparing the treatment decisions proposed by WFO with those of the multidisciplinary tumor board. Concordance was achieved when the oncologists' treatment decisions were in the recommended or for consideration categories in WFO. RESULTS: Ovarian cancer showed the highest concordance, which was 96%. Lung cancer and breast cancer obtained a concordance of slightly above 80%. The concordance of rectal cancer was 74%, whereas colon cancer and cervical cancer showed the same concordance of 64%. In particular, the concordance of gastric cancer was very low, only 12%, and 88% of cases were under physicians choice. CONCLUSION: Different cancer types showed different concordances, and only gastric cancers were significantly less likely to be concordant. Incidence and pharmaceuticals may be the major cause of discordance. To be comprehensively and rapidly applied in China, WFO needs to accelerate localization. ClinicalTrials.gov Identifier: NCT03400514. IMPLICATIONS FOR PRACTICE: IBM Watson for Oncology (WFO) has begun to be used in China. In this study, concordance was examined between the treatment recommendation proposed by WFO and clinical decisions for 362 patients in our cancer center, which could reflect the differences of cancer treatment between China and the U.S. Different cancer types showed different concordances, and only gastric cancers were significantly less likely to be concordant. Incidence and pharmaceuticals may be the major causes of discordance. To be comprehensively and rapidly applied in China, WFO needs to accelerate localization. This study may have a significant effect on application of artificial intelligence systems in China.

Celastrol inhibits growth and metastasis of human gastric cancer cell MKN45 by down-regulating microRNA-21.

Celastrol could inhibit cancer cell growth in vitro. However, effect(s) of celastrol on gastric cancer is not well studied. Therefore, we investigated the effects of celastrol on human gastric cancer cell line MKN45 and the underlying mechanisms. We found that celastrol inhibited cell proliferation, migration, and invasion and induced cell apoptosis and G2/M cell cycle arrest (p < .05, p < .01, or p < .001). Under celastrol treatment, overexpression of microRNA-21 (miR-21) increased cell viability, migration, and invasion and inhibited cell apoptosis compared with negative control (p < .05, p < .01, or p < .001). In addition, the phosphorylation of PTEN was significantly up-regulated, whereas PI3K, AKT, p65, and IκBα phosphorylation was statistically decreased by celastrol (p < .05 or p < .01) and then further reversed by miR-21 overexpression (p < .05 or p < .01). On the other side, miR-21 silence showed contrary results (p < .05) as relative to miR-21 overexpression. In conclusion, celastrol inhibits proliferation, migration, and invasion and inactivates PTEN/PI3K/AKT and nuclear factor κB signaling pathways in MKN45 cells by down-regulating miR-21.